1. Field of the Invention
This invention relates to an optically active pyranobenzoxadiazole compound, which is an important intermediate in the synthesis of an optically active pyranobenzoxadiazole derivative useful for the treatment of hypertension and asthma, and a process for the optical resolution of a pyranobenzoxadiazole compound.
2. Description of the Prior Art
A pyranobenzoxadiazole derivative represented by the formula [III] (which will be briefly referred to as the compound [III] hereinafter): ##STR3## wherien A represents a hydroxyl group or an OC(O)CH.sub.3-n X.sub.n group which X represents a fluorine atom, a chlorine atom, a bromine atom, a methyl group or a methoxy group and n represents 0 or an integer of 1 to 3;
when R.sup.1 represents a hydrogen atom, R.sup.2 represents a hydrogen atom, C(Z)CH.sub.3-n X.sub.n group, in which Z represents an oxygen atom or a sulfur atom and X and n is as defined above, or C(Z)NHCH.sub.3-n X.sub.n group, in which Z and n are defined above; and
when R.sup.1 does not represent a hydrogen atom, R.sup.1 and R.sup.2 together represent (CH.sub.2).sub.m-1 C(Z) group, in which m represent an integer of 4 or 5 and Z is as defined above, (CH.sub.2).sub.m-2 NHC(Z) group or a (CH.sub.2).sub.m-2 OC(Z) group, in which Z and m are as defined above,
is obtained in the form of a racemic mixture as described in Japanese Patent Laid-Open No. Hei 2-49788 (49788/1990) and U.S. Pat. No. 4,900,752. The compound III] exerts intense vasodilatory and hypotensive activities and thus is expected to be useful as a medicine for treating hypertension, angina pectoris, arrhythmia, cerebral circulation disorders and asthma.
As described in the Japanese Patent Laid-Open No. Hei 2-49788 (49788/1990), the compound [III] can be synthesized in the following manner: ##STR4##
In above reaction schemes, Y represents an leaving group such as a halogen atom (for example, a chlorine, bromine or iodine atom), an acetoxy group or a trifluoroacetoxy group;
Y.sup.1 represents a chlorine atom, a bromine atom, an iodine atom, an o- or p-toluenesulfonate group or a methanesulfonate group; and
m, n and X are as defined above.
The compound [A], which is a compound [III] wherein R.sup.1 represents a hydrogen atom, can be prepared by reacting a pyranobenzoxadiazole compound, which is obtained in the form of a racemic mixture (briefly referred to as the compound [(+) I] hereinafter), with an acylating agent YC(O)CH.sub.3-n X.sub.n, in which X, Y and n are as defined above, optionally in the presence of a base (refer to Reaction Scheme 1).
The compound [B], which is a compound [III] wherein R.sup.1 represents a hydrogen atom, can be prepared by reacting the compound [(.+-.)I] with an isocyanate C(O)NCH.sub.3-n X.sub.n or isothiocyanate X.sub.n CH.sub.3-n NC(S) in which X, Z and n are as defined above (refer to Reaction Scheme 2).
The compound [C], which is a compound [III] wherein R.sup.1 and R.sup.2 together represent (CH.sub.2).sub.m-1 C(O) group, can be prepared by reacting the compound [(.+-.)I] with an acylating agent YC(O)(CH.sub.2).sub.m-1 Y.sup.1, in which Y, Y.sup.1 and m are as defined above, optionally in the presence of a base and then cyclizing the reaction product optionally in the presence of a base (refer to Reaction Scheme 3).
The compound [D], which is a compound [III] wherein R.sup.1 and R.sup.2 together represent (CH.sub.2).sub.m-2 NHC(Z) group in which Z and m are as defined above, can be prepared by reacting the compound [(.+-.)I] with an isocyanate (O)CN(CH.sub.2).sub.m-2 Y.sup.1 or isothiocyanate (S)CN(CH.sub.2).sub.m-2 Y.sup.1, in which Y.sup.1 and m are as defined above, and then cyclizing the reaction product optionally in the presence of a base (refer to Reaction Scheme 4).
The compound [E], which is a compound [III] wherein R.sup.1 and R.sup.2 together represent (CH.sub.2).sub.m-2 OC(O) group in which m is as defined above, can be prepared by reacting the compound [(.+-.)I] with a halogenocarbonate YC(O)O(CH.sub.2).sub.m-2 Y . in which Y, Y.sup.1 and m are as defined above, optionally in the presence of a base and then cyclizing the reaction product optionally in the presence of a base (refer to Reaction Scheme 5).
In the above reaction schemes, a compound if [III] wherein Z is a sulfur atom may be obtained by sulfurizing the corresponding compound wherein Z is an oxygen atom with Lawesson's reagent.
As described in the Japanese Patent Laid-Open No. Hei 2-49788 (49788/1990), the compound [(.+-.)I] may be prepared in the following manner: ##STR5##
The compound [(.+-.)I] may be obtained by treating a known compound [F] with sodium hypochlorite, reducing N-oxide group of the compound [G] thus formed with a reducing agent such as triethyl phosphite and then reacting the compound [H] thus formed with ammonia in an inert solvent.
However, there has never been reported the optical resolution of the compound [(.+-.)I].
Furthermore, the above-mentioned racemic compound [III], which carries asymmetric carbon atoms at the 3- and 4-positions of the pyran ring, has two optical isomers (compound [III*] and [III**]). However, the above Japanese Patent Laid-Open No. Hei 2-49788 (49788/1990) describes neither these optically active pyranobenzoxadiazole derivatives nor any process for the production of the same.
In the field of medicines, it is frequently observed that optical isomers are different from each other in pharmacological activity and safety. Therefore, it is desirable to optically resolve these isomers in order to develop better medicines.
The present inventors have found out that an optically active pyranobenzoxadiazole derivative (corresponding to the compound [III*]), which is synthesized via an optically active pyranobenzoxadiazole compound showing dextrorotation in ethanol (corresponding to the compound [(.+-.)I] which will be described hereinafter), is remarkably superior to an optically active pyranobenzoxadiazole derivative (corresponding to the compound [III**]), which is synthesized via an enantiomer (corresponding to the compound [(-)I] which will be described hereinafter), from the viewpoint of medicinal activities, thus completing the present invention.